Submissions for variant NM_139276.3(STAT3):c.1144C>T (p.Arg382Trp)

dbSNP: rs113994135

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000259784	SCV000329539	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21606497, 23040277, 22581330, 22500887, 24452316, 17881745, 23830147, 32248557, 27315770, 21324546, 17942886, 21288777, 17676033, 26384563, 26293184, 20093388, 27799162, 4161105, 29620631, 30697212, 30410549, 30732127, 31346092, 31596517, 31681265, 32047500, 32135276, 32912316, 32768442, 33343952, 32915432, 33225392, 32944025, 32888943, 33014947, 34134972, 33717144, 18602572)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000019966	SCV000890890	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2016-12-20	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000259784	SCV000928166	pathogenic	not provided	2019-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000814004	SCV000954392	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3 gain of function	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 382 of the STAT3 protein (p.Arg382Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (HIES) (PMID: 17676033, 17881745, 17942886, 21324546, 24452316). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STAT3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 17676033, 22581330). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000259784	SCV001246596	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000019966	SCV001428723	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2019-06-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000019966	SCV001519765	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2020-05-08	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000019966	SCV002521168	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000018304) and a different missense change at the same codon(p.Arg382Gln; ClinVar ID: VCV000018305) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	RCV003149573	SCV003837575	pathogenic	STAT3-related early-onset multisystem autoimmune disease	2023-01-03	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795931	SCV005417346	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant; STAT3-related early-onset multisystem autoimmune disease		criteria provided, single submitter	clinical testing	PS3+PM6+PS4_Moderate+PM5+PM2_Supporting+PP4
OMIM	RCV000019966	SCV000040264	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2007-10-18	no assertion criteria provided	literature only
GeneReviews	RCV000019966	SCV000041586	not provided	Hyper-IgE recurrent infection syndrome 1, autosomal dominant		no assertion provided	literature only
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000019966	SCV002573432	pathogenic	Hyper-IgE recurrent infection syndrome 1, autosomal dominant	2022-05-01	no assertion criteria provided	clinical testing